This invention relates to a novel method for the chemical synthesis of 1,5-dideoxy-1,5-imino-D-mannitol and the corresponding L-mannitol derivative. ##STR1## 1,5-Dideoxy-1,5-imino-D-mannitol ##STR2## 1,5-Dideoxy-1,5-imino-L-mannitol
In order to show stereoisomerism, solid and dotted lines show bonds directed above or below, respectively, the plane of the paper.
1,5-Dideoxy-1,5-imino-D-mannitol, also known as deoxymannojirimycin, is a potent mannosidase inhibitor. It is also useful in the production of inhibitors of the human immuno-deficiency virus as described in co-pending applications Ser. Nos. 136,219 and 136,224, both filed Dec. 21, 1987.
The conventional synthesis of 1,5-dideoxy-1,5-imino-D-mannitol and the corresponding L-gulo derivative is described by Legler and Julish, Carbohydr. Res. 128, 61-72 (1984). They carried out the synthesis in essentially 7 steps from 2,3:5,6-di-O-isopropylidene-.alpha.-D-mannofuranose, which can be described briefly as follows:
A. Reaction of 2,3:5,6-di-O-isoproylidene-.alpha.-D-mannofuranose with benzyl chloride to produce benzyl 2,3:5,6-di-O-isopropylidene-.EPSILON.-D-mannofuranoside (1).
B. Selective removal of the 5,6-isopropylidene protecting group from compound (1) by HCl in methanol to give the benzyl 2,3-O-isopropylidene-.alpha.-D-mannofuranoside (2).
C. Reaction of compound (2) with trityl chloride in pyridine to provide benzyl 2,3-O-isopropylidene-6-O-trityl-.alpha.-D-mannofuraoside (3).
D. Oxidation of compound (3) with methyl sulfoxide-acetic anhydride to produce as a main product the ketone benzyl 2,3-O-isopropylidene-6-O-trityl-.alpha.-D-lyxo-hexofuranoside-5-ulose (4) and a by-product (5) identified as the 5-O-methylthiomethyl derivative of compound (3).
E. Conversion of the ketone compound (4) into the oxime and reduction with Raney nickel to give a mixture of compound (6a) having the D-manno configuration, namely benzyl 5-amino-5-deoxy-2,3-O-isoproylidene-6-O-trityl-.alpha.-D-mannofuranoside, and compound (6b) having the L-gulo configuration, namely, the corresponding -.alpha.-L-gulofuranoside.
F. Trityl cleavage of compounds (6a) and (6b) with HCl in methanol to provide benzyl 5-amino-5-deoxy-2,3-O-isopropylidene-.alpha.-D-mannofuranoside (7a) and the corresponding -.alpha.-L-gulofuranoside (7b).
G. Deprotection of compound 7a and rearrangement to the desired six-membered cyclic derivative was carried out as follows: Reductive debenzylation of compound (7a) by hydrogenation using a catalyst prepared from palladium hydroxide on charcoal followed by cleavage of the isopropylidene group with HCl to yield 1,5-dideoxy-1,5-imino-D-mannitol (12a). Corresponding hydrogenation of compound (7b) gave 1,5-dideoxy-1,5-imino-L-gulitol (12b).
The enantiospecific synthesis of D-deoxymannojirimycin from D-glucose is described by Fleet and Smith, Tetrahedron Lett. 26, 1469-1472 (1985). According to this synthesis, D-glucose is converted to the azidomannofuranoside which is then cyclised by intramolecular nucleophilic attack on C-6 to the bicyclic amine in which the original C-5 hydroxyl of glucose is unprotected. That is, the formation of the piperidine ring is achieved by intramolecular nucleophilic displacement of a leaving group at C-6 by an amino group at C-2. Thus, the primary hydroxyl group in the azidodiol was selectively tosylated and the sulfonate ester was hydrogenated in the presence of palladium black. The resulting amine was treated with sodium acetate in ethanol, and subsequently with benzyl chloroformate, to give the bicyclic benzyl carbonate. Hydrolysis of the acetal function in the latter compound by aqueous trifluoroacetic acid, followed by reduction with sodium borohydride gave ##STR3## Removal of the benzyl (OCH.sub.2 Ph) and benzyloxycarbonyl (Z) protecting groups by hydrogenolysis with palladium hydroxide catalyst gave D-deoxymannojirimycin.
Other such lengthy stepwise syntheses of D-deoxymannojirimycin from D-mannose or D-glucose and their derivatives are described by Fleet et al., Tetrahedron Lett. 25, 4029-4032 (1984); Fleet et al., Tetrahedron 43, 979-990 (1987); and Leontein et al., Acta Chem. Scand. Ser. B, B36(8), 515-518 (1982).
While the foregoing methods for the production of D-deoxymannojirimycin are useful, synthesis of the desired compound in fewer steps and in substantial yield would be of significant value.